Sertraline hydrochloride (trade names Zoloft , Lustral ) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive-compulsive, panic and social anxiety disorders in both adults and children. In 2007 it was the most prescribed antidepressant on the US retail market, with 29,652,000 prescriptions.
The efficacy of sertraline for depression is similar to that of older tricyclic antidepressants, but its side effects are much less pronounced. Differences with newer antidepressants are subtler and also mostly confined to side effects. Evidence suggests that sertraline may work better than fluoxetine (Prozac) for some subtypes of depression. Sertraline is highly effective for the treatment of panic disorder, but cognitive behavioral therapy is a better treatment for obsessive-compulsive disorder, whether by itself or in combination with sertraline. Although approved for social phobia and posttraumatic stress disorder, sertraline leads to only modest improvement in these conditions. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.
Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects; however, it does not cause weight gain, and its effects on cognition are mild. In pregnant women taking sertraline, the drug was present in significant concentrations in fetal blood, and was also associated with a higher rate of various birth defects. Similarly to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidality. Due to the rarity of this side effect, statistically significant data is difficult to obtain, and suicidality continues to be a subject of controversy.
History
The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds based on the structures of neuroleptics chlorprothixene and thiothixene. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type—in that sense their inquiry was not "very goal driven", and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even "did not have a formal project team". The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.
Sertraline was approved by the U.S. Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, Director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect on outpatients with depression had been "modest to minimal". Other experts emphasized that the drug's effect on inpatients had not differed from placebo and criticized poor design of the trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.
Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data). It was measured as among the top ten drugs ranked by cost to the Australian government in 1998 and 2000–01, having cost $45 million and $87 million in subsidies respectively. Sertraline is less popular in the UK (2003 data) and Canada (2006 data)—in both countries it was fifth, based on the number of prescriptions.
Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe obsessive-compulsive disorder (OCD). In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (trade name Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a black box warning concerning pediatric suicidality to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidality in young adults ages 18 to 24.
The U.S. patent for Zoloft expired in 2006, and sertraline is now available in generic form.
Indications
Sertraline has been approved for the following indications: major depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder and social phobia (social anxiety disorder).
Depression
The original pre-marketing clinical trials demonstrated only weak-to-moderate efficacy of sertraline for depression. Nevertheless, a considerable body of later research established it as one of the drugs of choice for the treatment of depression in outpatients. Despite the negative results of early trials, sertraline is often used to treat depressed inpatients as well. Sertraline is effective for both severe depression and dysthymia, a milder and more chronic variety of depression. In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia and comparable to imipramine (Tofranil) in that respect. Sertraline also improved the depression of dysthymic patients to a greater degree than group cognitive behavioral therapy or interpersonal psychotherapy, and adding psychotherapy to sertraline did not seem to enhance the outcome. These results also held up in a two-year follow-up of sertraline-treated and interpersonal-therapy-treated groups. In the treatment of depression accompanied by OCD, sertraline performed significantly better than desipramine (Norpramine) on the measures of both OCD and depression. Sertraline was equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it was better tolerated. Sertraline treatment of depressed patients with co-morbid personality disorders improved their personality traits, and this improvement was almost independent from the improvement of their depression.
Comparison with tricyclic antidepressants
The effect of sertraline on the core symptoms of depression is similar to that of tricyclic antidepressants (TCAs); however, it is better tolerated and results in a better quality of life. Similar improvement of depression scores was seen in studies comparing sertraline with clomipramine (Anafranil) and amitriptyline (Elavil). At the same time, sertraline resulted in a much lower rate of side effects than amitriptyline (49%, vs. 72% for amitriptyline and 32% for placebo), particularly dry mouth, somnolence, constipation and increased appetite. However, there were more cases of nausea and sexual dysfunction in the sertraline group. Participants taking sertraline showed a greater improvement of the subjective quality of life on such measures as work satisfaction, subjective feeling, perceptions of health and cognitive function.
A large and thorough double-blind study compared sertraline—prescribed for chronic (longer than two years) depression or depression with dysthymia—to the "gold standard" of depression treatment, the TCA imipramine (Tofranil). Sertraline was equivalent to imipramine for both of these indications during the first 12 weeks of the study and the 16-week continuation phase. Only 11% of patients on sertraline suffered from severe side effects vs. 24% on imipramine. Constipation, dizziness, tremor, dry mouth, micturition disorder and sweating were observed more often with imipramine, and diarrhea and insomnia with sertraline. Patients on sertraline also reported significantly better social and physical functioning. The 30% of the patients treated with sertraline or imipramine who achieved a remission during the trial did not differ from the healthy population on the measures of marital, parental, physical and work functioning and were close to normal on
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